Esters and amides of 2-phenyl-bicyclo-(2, 2, 1) heptane-2-carboxylic acid, 2-phenyl-bcyclo(2, 2, 1)-5-heptene-2-carboxylic acid, 2-phenyl-bicyclo(2, 2, 2)-5-octene-2-carboxylic acid and 2-phenyl-bicyclo(2, 2, 2)octane carboxylic acid



United States Patent ESTERS AND AMIDES OF Z-PI-ENYL-BICYCLO-(2,2,1)HEITANE-2-CARBOXYLIC ACID, Z-PEEN- YL-BICYCLO(2,2,1)S-HEPTENE-Z-CARBOXYLIC ACID, Z-PHENYL BICYCLO(2,2,2)-5-0CTENE-2-CARBOXYLIC ACID AND Z-PHENYL-BICYCLO- (2,2,2)OCTANE CARBOXYLIC ACIDWilfrid Klavehn, Schwetzingen, and Helmut Kraft, Mannheim, Germany,assiguors to Knoll A.-G. Chemische Fabriken, Ludwigshafen (Rhine),Germany, a corporation of Germany N0 Drawing. Filed June 10, 1957, Ser.No. 664,472 Claims priority, application Germany June 16, 1956 15Claims. (Cl. 260292) The present invention relates to therapeuticallyvaluable rbasic esters and acid amides and more particularly to basicesters and acid amides derived from 2-phenyl acrylic acid, and to aprocess of making same.

It is one object of the present invention to provide new and valuablebasic esters and amides of carboxylic acids which are derived from2-phenyl acrylic acid and which possess important therapeutically usefulproperties, such as spasmolytic and ganglia-blocking properties.

Another object of the present invention is to provide a simple andeifective process of converting Z-phenyl acrylic acid intotherapeutically valuable esters and amides of new carboxylic acids.

Still another object of the present invention is to pro vide 2-phenylbicyclo(2,2,1)heptane-2-carboxylic acid-wtertiary amino (lower) alkylesters which have proved to be valuable therapeutic agents.

A further object of the present invention consists in providing new andvaluable 2-bicyclic(2,2,1)heptane-2- carboxyl-ic acid esters withheterocyclic alcohols which possess valuable therapeutic properties.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

In principle, the valuable basic esters and acid amides according to thepresent invention are esters and amides of carboxylic acids of thefollowing Formula I l-C 0 OH Y Z In said formula The new basic estersand amides of carboxylic acid of Formula I are obtained by reacting2-phenyl acrylic acid or its functional derivatives, especially itsesters and its nitrile, with a diene hydrocarbon and converting theresulting unsaturated adducts into their basic esters or acid amides orthe quaternary ammonium salts of such "basic esters, or amides. Suchbasic esters or amides are prepared -by reaction of the resulting newcarboxylic acids or their functional derivatives, such as their metalsalts, esters, amides, halogenides, with tertiary amino alcohols or "icetertiary amino alkyl amines, such as dialkylamino alcohols, dialkylaminoalkyl amines, or alcohols or amines of heterocyclic compounds having anitrogen atom in their heterocyclic nucleus. Preferred reactioncomponents are dialkylamino alcohols and dialkylamino alkyl amineswherein the alkyl radicals are low-molecular alkyl radicals.

The preferred tertiary amino alcohols or tertiary aminoalkylamines usedfor the purpose of the present invention are amino alcohols oraminoalkylamines with 2 or 3 carbon atoms in their alkyl chain.

Double bonds which are present in the alicyclic ring formed by thesubstituents Y and Z together with the carbon atom to which they areattached, may be hydrogenated either before or after the basic residueis introduced into the molecule.

Reaction of 2-phenyl acrylic acid or its functional derivatives, such asits esters or its nitrile, with diene compounds such as butadiene,isoprene, dimethyl butadiene, phenyl butadiene, cyclopentadiene,cyclohexadiene, aphellandrene, and the like yields the new class ofunsaturated compounds according to the present invention, such as the1-phenyl-3-cyclohexene-1-carboxylic acids of Formula II, the 2-phenyl'bicyclo(2,2,l)-5-heptene-2-carboxylic acid of Formula III, or theZ-phenyl-bicyclo (2,2,2)-5-octene-2-carboxylic acids of Formula IV,wherein R and R indicate the same substituents as mentioned hereinabove.

C O O H R3 (III) C O O H R2- C 2 s (IV) A \l The basic ester componentsof the new basic esters according to the present invention are residuesof tertiary amino alcohols and preferably tertiary amino alcohols whichare substituted at their nitrogen atom by lowmolecular alkyl radicals,such as dialkylamino ethanols or dialkylamino propanol or residues ofheterocyclic alcohols having a nitrogen atom in their heterocyclic nu- 1cleus, such as the pyrrolidino, piperidino, morpholino ethanols andpropanols or tertiary 4-piperidols, tropinol or the like.

The basic amide components of the new amides of the above mentionedacids are residues of tertiary amino alkylarnines which are substitutedat their tertiary nitro gen atom by low-molecular alkyl radicals such asdialkylamino ethylamines or dialkylamino propylamines, or diamines, theone nitrogen atom of which is a member of a heterocyclic nucleus, suchas pyrrolidino ethylamine, piperidino ethylamine, morpholino ethylamine,or the corresponding propylamines.

According to the present. invention either the free acids mentionedhereinabove or their esters or nitriles are used as starting materialsinthe production of the basic esters or amides.

'For instance, the basic esters are obtained by first converting themonocyclic or bicyclic carboxylic acids mentioned hereinabove into theiracid halogenides or esters which are then reacted with the abovementioned tertiary amino alcohols. Or the acids or their metal salts candirectly be reacted with the corresponding tertiary amino alkylhalogenides to form the desired basic esters.

The basic amides according to the present invention are prepared byfirst converting the above mentioned carboxylic acids into their acidhalogenides or their esters which are then reacted with ammonia orprimary amines to form the corresponding amides which are subsequentlyreacted with tertiary amine alkyl halogenides corresponding to the abovementioned tertiary amino alcohols. The reaction with said tertiary aminoalkyl halogenides is preferably carried out in the presence of alkalineagents.

Another method of producing the basic amides consists in reacting thehalogenides or esters of the above mentioned carboxylic acids withdialkylamino .alkylamines or with diamines wherein one of the nitrogenatoms of said amino groups is a member of a heterocyclic nucleus.

In order to convert the monocyclic or bicyclic carboxylic acid estersinto the basically substituted corresponding esters or amides, thestarting esters are either directly reacted with the above mentionedtertiary amino alcohols or tertiary amino alkylatnines or they are firstconverted, by saponificatiom'into the free acids which are then reacted,as described hereinabove, to form the corresponding basic compoundsaccording to the present invention. When starting with monocyclic orbicyclic nitriles, they are preferably first converted bysaponification, into the free acids and said acids or their esters arethen reacted, as described hereinabove, to yield the desired basicesters or amides.

It is also possible and has proved to be of great advantage to firstprepare the corresponding basic ester or .acid amide of 2-pheny1 acrylicacid which is then reacted with a diene hydrocarbon, thereby alsoproducing the desired esters and amides. This simple process ofproducing the new compounds according to the present inventionrepresents a novel and advantageous method of making said compounds.

Especially valuable compounds obtained according to the presentinvention are the following compounds:

(I) Z-Phenyl Bicyclo(2,2,1)Heptane-Z-Carboxylic Acid Diethylamino PropylEster This compound is prepared by reacting the acid chlo-- ride ofZ-phenyl bicyclo(2,2',1)heptane-Z-carboxylic acid with -diethylaminopropanol as described hereinafter in Example 7. The resulting ester hasa high antichlorinergic activityzand at the same time a highlyantagonitsic eifect against spasms caused by exposing an isolated pieceof the gut of a guinea pig to the action of barium chloride. In thistest the new compound is superior to atropine. Especially noteworthy is,furthermore, its high antagonistic efiect against nicotine. Itsanti-nicotinic activity is superior to and more prolonged than that ofthe known agents used in the treatment of parkinsonism,

such as atropine or the tropine benzohydryl ether methane sulfonate.

(2) Z-Phenyl Bicycl0(2,2,1)Heptane-Z-Carboxylic Acid T ropinol EsterThis compound is obtained by reacting the acid chloride of Z-phenylbicyclo(2,2,1)heptane-Z-carboxylic acid with tropinol as describedhereinafter in Example 7. It has a stronger anticholinergic activitythan any of the known anticholinergic agents. Furthermore, it differsfrom other comparable compounds of this type by its high antiphlogisticactivity. Therefore, it is a valuable therapeutic agent which has beensuccessfully employed in the treatment of inflammatory skin diseasesaccompanied by itching, for instance, in the treatment of eczema and thelike.

(3) 2-Phenyl Bicyclo(2,2,1)Heptane-Z-Carboxylic Acid-N-rWethyll-Piperidol Ester Metho Sulfate This compound is preparedaccording to Example 7 given hereinafter. It has a noteworthy inhibitingeffect upon gastric juice secretion.

Other basic esters and amides according to the present invention possessalso valuable therapeutic properties and are, for instance, highlyeffective spasmolytic, gangliablocking, and the like agents.

The starting materials used for making the basic esters or amides of thenew acids of the formua given hereinabove, i.e. the adducts of dienehydrocarbons to 2-phenyl acrylic acid or its functional derivatives, arenew and valuable intermediates useful in the preparation of the abovementioned therapeutically active basic esters and amides.

Reaction of Z-phenyl acrylic acid or its functional derivatives withdiene compounds is carried out under presture and at elevatedtemperature. Preferably a solution of 2-phenyl acrylic acid, its esters,or its nitrile and the diene compound in an inert high-boiling solvent,for instance, an aromatic hydrocarbon, such as Xylene, is carried out ata temperature between about C. and 150 C. Heating at a temperaturebetween about 100 C. and about 150 C. and preferably at a temperature ofabout C. has proved to be especially suitable. Other solvents thanxylene may also be used, provided their boiling point is high enough topermit heating to the reaction temperature without the generation of toohigh a. pressure in the autoclave.

Side-reactions, as they are caused by polymerization of the dienecompounds or by mixed polymerization of the diene compounds and the2-phenyl acrylic acid or its derivatives are preferably suppressed bythe addition of a suitable inhibitor, such as hydroquinone,diphenylamine, pyrogallol, and other inhibitors known to the art.

referably the diene synthesis is carried out in a nitrogen atmosphere.

It is quite surprising that the 2-phenyl acrylic acid and its functionalderivatives can be subjected to the diene synthesis; for, it is knownthat said acids and their esters are readily polymerized on heating.They form thereby isatropic acid derivatives, which are unsuitable fordiene condensation. Due to their easy polymerizability it could beexpected that, on heating the reaction mixture, first such isatropicacid derivatives would be formed and not the desired diene adductsaccording to the present invention. That the 2-pheny1 acrylic acid is.readily polymerizable, has been reported, for instance, by Baker andEccles, Journ. Chem. Soc. London, vol. 1927, page 2129. Thus, the newdiene synthesis according to the present invention represents a noveland entirely unexpected reaction.

The following examples serve to illustrate the presentinvention,.without, however, limiting the same thereto.

The exact constitution of the compounds, obtained according to Examples2 and 4, has not yet been determined with certainty. The possiblepositions of the methyl or,

respectively, phenyl substituent are indicated in said examples.

EXAMPLE 1 (a) 1-Phenyl-3-Cycl0hexene-1-Carb0xylic Acid Ethyl Ester Asolution of 380 g. of 2-phenyl acrylic acid ethyl ester and 175 g. ofbutadiene in 220 cc. of xylene is heated with the addition of 4 g. ofhydroquinone in an autoclave at 130 to 150 C. for 12 hours whilestirring. After cooling the clear solution of the reaction mixture isheated in a vacuum on a water bath, the solvent is evaporated, and theresidue is subjected to fractional distillation in a vacuum by means ofa fractionating column. First unreacted 2-phenyl acrylic acid ethylester of the boiling point 96 C. to 99 C./4 mm. distills over and isrecovered. Thereafter, the reaction product itself, the 1-phenyl-3-cyclohexene-l-carboxylic acid ethyl ester of the formula C H Odistills at 133 C. to 136 C./4 mm. in the form of a colorless refractiveoil of pleasant odor.

(b) 1-Phenyl-3-Cyclohexene-l-Carb0xylic Acid-B- Diethylamino Ethyl EsterA solution of 23 g. of said 1-phenyl-3-cyc1ohexene-1- carboxylic acidethyl ester in 65 cc. of toluene is gradually added drop by drop to agently boiling mixture of 17 g. of diethylamino ethanol, 180 cc. oftoluene, and 0.2 g. of metallic sodium. The reaction takes place in athree-necked flask provided with a fractionatiug column and a descendingcondenser. When no more ethanol distills off, the residue is shaken andextracted with 2 N hydrochloric acid. The basic ester is precipitatedfrom the hydrochloric acid solution by the addition of sodium hydroxidesolution and the precipitate is dissolved in ether. The resultingB-diethylamino ethyl ester of 1-phenyl-3-cyclohexene-l-carboxylic acidof the formula C H O N boils at 133134 C./0.2 mm. Its hydrochloric meltsat 160 l61 C. on recrystallization from a mixture of ethanol and ether(1:1).

EXAMPLE 2 (a) 1-Phenyl-3-Methyl-3-Cycl0hexene-l-Carboxylic Acid EthylEster or, Respectively, 1-Phenyl-4-Methyl-3- Cyclohexene-I-Carb0xylicAcid Ethyl Ester A solution of 380 g. of 2-phenyl arcylic acid ethylester and 224 g. of methyl butadiene in 250 cc. of xylene is heated withthe addition of 4 g. of hydroquinone in an autoclave at 150 C. for about12 hours, while 'stirring. After cooling, the clear solution of thereaction mixture is heated in a vacuum on a water bath. The solvent isevaporated and the residue is subjected to fractional distillation in avacuum While using a fractionating column. First unreacted 2phenylacrylic acid ethyl ester of the boiling point 96 C. to 99 C./4 mm.distills over and is recovered. Thereafter, l-phenyl-3-methyl-3-cyclohexene-1-carboxylic acid ethyl ester, or, respectively,1-phenyl-4-methyl-3-cyclohexene-l-ca.rboxylic acid ethyl ester of theformula C H O is collected; said ester boils at 147 C. to 149 C./4 mm.and is obtained in the form of a faintly yellowish refractive oil.

(b) 1-Phenyl-3-Methyl-3-Cyclohexene-1 -Carb0xylic Acid- B-DiethylamineEthyl Ester 0r, Respectively, I-Phenyl-4-Me'thyl-3-CycI0hexene-1-Carb0xylic Acid-fl-Diethylamino Ethyl Ester Asolution of 22.4 g. of the 1-phenyl-3 or, respectively,4-methyl-3-cyclohexene-1-carboxylic acid methyl ester in 65 cc. oftoluene is slowly added drop by drop to the gently boiling mixture of 17g. of diethylamino ethanol, 180 cc. of toluene, and 0.2 g. of metallicsodium. The reaction is carried out in a three-necked flask providedwith a fractionating column and a descending condenser. When no moreethanol distills off, the residue is shaken with 2 N hydrochloric acid,the basic ester is precipitated from the resulting hydrochloric acidsolution by 6 the addition of sodium hydroxide solution, and theprecipitate is dissolved in ether. The resulting basic ester of theformula C H O N boils at 155 C. to 161 C./0.15 mm. Its hydrochloridemelts, on recrystallir: ation from a mixture of ethanol and ether (1:1),at 139 C. to 140 C.

EXAMPLE 3 (a) 1-Phenyl-3,4-Dimethyl-3-Cycl0hexene-1-Carboxylic AcidEthyl Ester A solution of 228 g. of 2-phenyl acrylic acid ethyl esterand 114 g. of 2,3-dimethyl butadiene in 200 cc. of xylene is heated withthe addition of 2 g. of hydroquinone in an autoclave as described inExample 2. The reaction mixture is worked up by following the procedureof said Example 2. The resulting 1-phenyl-3,4-dimethyl-3-cyclohexene-1-carboxylic acid ethyl ester of the formula C H O is afaintly colored refractive oil of the boiling point 143 C. to 146 C./4mm.

(b) 1 -Phenyl3,4-Dimethy l-3-Cycl0hexene-1 -Carb0xylicAcid-tt-Diethylamino Ethyl Ester Reacting said 1-phenyl-3,4-dimethyl-3cyclohexene-1- carboxylic acid methyl ester with diethylamino ethanol byfollowing the procedure described in Example 2, yields1-phenyl-3,4-dimethyl-3-cyclohexene l-carboxylic acid-B-diethylaminoethyl ester of the formula C H O N, boiling at 146 C./0.2 mm. Itshydrochloride melts, on recrystallization from the mixture of ethanoland ether (1:1), at 161-162 C.

EXAMPLE 4 (a) l,5-Diphenyl-3-Cycl0hexene-1-Carboxylic Acid Ethyl Esteror, Respectively, 1,2-Diphenyl-3-Cycl0hexenel-Carboxylic Acid EthylEster A solution of 176 g. of 2-phenyl acrylic acid ethyl ester and 130g. of l-phenyl butadiene in 200 cc. of xylene is heated in an autoclavewith the addition of 1 g. of diphenylamine as described hereinabove inEx ample 2. The reaction mixture is worked up by follow- 'ing theprocedure as described in said Example 2. The resulting 1,5- or,respectively, 1,Z-diphenyl-3-cyclohexenel-carboxylic acid ethyl ester isa viscous, fluorescent oil of the boiling point 198 C. to 200 C./ 4 mm.

(b) 1,5- or 1,2-Diphenyl-3-Cycl0hexene-1-Carb0xylic Acid-B-DiethylaminoEthyl Ester On reacting said ester with diethylamino ethanol accordingto Example 2, 1,5- or, respectively, 1,2-diphenyl-3-cyclohexane-l-carboxylic acid-,B-diethylamino ethyl ester of theformula C H O N is obtained. Its boiling point is 187 to 191 C./0.2 mm.

EXAMPLE 5 (a) 2-Phenyl-Bicycl0(2,2,1)Heptane-2-Carb0xylic Acid Asolution of 222 g. of 2-phenyl acrylic acid and g. of cyclopentadiene in200 cc. of xylene is heated with the addition of 2 g. of hydroquinone inan autoclave at 150 C. for about 12 hours while stirring. After cooling,the reaction mixture is treated with dilute sodium hydroxide solution.The resulting aqueous alkaline solution is separated from the organicsolvent layer and is repeatedly extracted with ether. On acidifying theextracted aqueous alkaline solution by the addition of dilutehydrochloric acid, a dark oil precipitates which is dissolved in ether.The ethereal solution is dried oven magnesium sulfate. After evaporatingthe ether, the residue is catalytically hydrogenated in methanolicsolution in the presence of Raney nickel catalyst at room temperatureand under pressure and the saturated acid obtained thereby is subjectedto fractional distillation after removing the catalyst. 2-phenylbicyclo(2,2,1)heptane-Z-carboxylic acid of the formula C H O distills inthe form of a colorless, viscous oil at a temperature of 168-175 C./4

mm. Said oil completely solidifies in the collecting flask. Onrecrystallization from hexane, its melting point is l48-149 C.

(b) Z-Phenyl Bicycl(2,2,1 )Heptane-Z-Carboxylic Acidfl-DiezhyfaminoEthyl Ester EXAMPLE 6 Z-Phenyl Bicycl0(2,2,l)-5-Heptene-2-CarboxylicAcid- ,B-Dierhylamino Ethyl Ester A solution of 486 g. of 2-phenylacrylic acid methyl ester and 298 g. of cyclopentadiene in 300 cc. ofxylene is reacted with the addition of g. of hyd-roquinone as describedin Example 2. The reaction mixture is worked 7 up by following theprocedure also described in said Example 2. The'resulting 2-phenylbicyclo(2,2,1)-5-heptene-Z-carboxylic acid methyl ester of the formula CH O is a colorless oil which boils at 140142 C./ 3 mm.

Reaction of said ester with diethylamino ethanol as describedherein-above in Example 2 yields 2-phenyl bicyclo( 2,2,1-5-heptene-2-carboxylic acid-fi-diethylamino ethyl ester of the formulac H O N boiling at 155-156 C./ 0.3 mm. Its hydrochloride melts, onrecrystallization from a mixture of ethanol and ether (1:1), at 168-170C. Its methosulfate of formula C I-1 N0 8 melts, on re crystallizationfrom a mixture of acetone and acetic acid ethyl ester (1:1 at 85-90 C.

Hydrogenation of Z- henyl bicyclo(2,2,1)-5-heptene-2- carboxylic acidmethyl ester in mcthanolic solution with the addition of Raney nickelcatalyst at room temperature and at a pressure of 100 atm. gauge yieldsthe saturated 2-phenyl bicyclo(2,2,1)heptane-Z-carboxylic acid methylester of the formula 0 E 0; in the form of a colorless oil which boilsat 108-112" C./0.4 mm.

Reacting said Z-phenyl bicyclo(2,2,1)heptane-Z-carboxylic :acid methylester with the following tertiary B- amino ethanols as describedhereinahove in Example 2,

a after a short period of time.

8 phenyl bicyclo(2,2,1)-5-heptene-2-carboxylic acid ethyl ester of theformula 0 E 0, is a colorless refractive oil of the boiling point140-146 C./ 4 mm.

Hydrogenation of said ester in methanolic solution by the addition ofR-aney nickel catalyst at room temperature and at a pressure of atm.gauge yields the saturated ethyl ester of the formula C d- 0 in the formof a colorless oil which boils at -127 C./ 3 mm.

A solution of 192 g. of said ester in 1500 cc. of a 15% methanolicpotassium hydroxide solution is boiled under reflux for 12 hours. Thesolution is concentrated by evaporation in a vacuum. 500 cc. of waterare added to the residue. On acidifying the mixture with hydrochloricacid, the free acid is obtained which melts at 148-149 C., onrecrystallization from hexane. V 60 g. of said acid are boiled underreflux with 100 g. of thionylchloride for 16 hours. After distilling offexcess thionylchloride, the corresponding acid chloride of the formula CH OCl, boiling at 164170 C./l4 mm., is obtained.

A solution of 35.2 g. of said acid chloride and 44.5 g. ofN-methyl-4-piperidol in 100 cc. of toluene is boiled under reflux for 12hours. 200 cc. of water are added to the reaction mixture. The organicsolvent layer is repeatedly shaken with water and then extracted with 2-N hydrochloric acid. The base is precipitated from the acid extracts bythe addition of sodium hydroxide solution and is dissolved in ether.From the etheral solution there is obtained the 2-phenylbicyclo(2,2,1)heptane-Z-carboxylic acid-N-mehhyl-4-piperidol ester ofthe formula C H O N which boils at -142 C./0.1 mm. and which, onrecrystallization from ligroin, melts at 8688 C. Its hydrochloridemelts, on recrystallization from a mixture of ethanol and ether (121),at 200 C.

To produce therefrom the methosulfate, 3.7 g. of dimethylsulfate areadded to a solution of 8.7 g. of said basic ester in 10 cc. of'aceticacid ethyl ester while cooling with ice. The quaternary ammoniumsalt crystallizes It corresponds to the formula C H O NS and melts, onrecrystallization from a mixture of acetic acid ethyl ester and ethanol(1:1), at 167l68 C.

By reacting tropinol with the acid chloride in the same manner asdescribed hereinabove for the reaction with N-methyl-4-piperidol, thereis obtained the tropinol ester of the formula C QH O N which boils at198-l99 C./ 4

Z-Phenyl Bicycl0(2,2,1)Heptane-Z-Carboxylic Acid- N-Methyl-4-PiperidolEster yields the following basic esters: mm. Its hydrochloride melts, onrecrystallization from Basic Ester Reaction with Derivatives FormulaBoiling Point Melting Point of Hydrochloride B-Dimethylamino ethanolClsH150rN 167170 C. (5 mm.)-. ELIE/Q5105 (from etha- V no 2 erB-Diethylarnino ethanol CzoHzsOzN.-.- 174-180 C. (3 mm.)-. I'll-173 CMethosult'ate n aaNOuS Melt. Pt. 75- 78 C. (from acetic acid ethylester). B-Dlethylamlno ethoxy ethanol C22 Ha30aN 170-175 C. (0.3 m6Piperidino ethanol CnHnOaN 204-210 C. (8 mm.) 175417651103 (from ethanoe er B-Morpholino ethanol C2oH2703N.-. 215220 C. (5 min-)0";17841795110.) (from ethano e er fi-Pyrrolldino ethanol C2oHs7O:N 155-160C. (0.2 mm.) 0. (from ethanol/ Ptcrate: Melt.

er) Pt. 143150 C. (trorn ethanol).

EXAMPLE 7 a mixture of ethanol and ether (1:1), at 224 C. Its

methosulfate of the formula C H O NS melts, on recrystallization fr'om amixture of ethanol and acetic acid ethyl ester,(l:1), at 215-216" C.

On reacting said acid chloride with 'y-diethylamino propanol, thecorresponding 'y-diethylamino propyl ester of the formula C H O N isobtained. Its boiling point is 159164 C./ 0.2 mm. Its hydrochloridemelts, on recrystallization from ethanol, at -151" C.

On reacting said acid chloride with N-ethyl piperidol,

2-phenyl bicyclo(2,2,1 )heptane-Z-carboxylic acid-N-ethyl- 4-piperidolester of the formula C H O N is obtained. Said ester boils at 165-168C./ 0.3 mm. Its hydrochloride melts, on recrystallization from a mixtureof ethanol and ether (1:1), at 176177 C. Its methosulfate of the formulaC H O NS melts, on recrystallization from a mixture of acetic acid ethylester and ethanol (1:1), at 143-144 C.

On reacting said acid chloride with S-isoocetenyl methylamino ethanol,there is obtained in an analogous manner as described hereinabove, the8-(2 methyl-2-hep-tenyl-6)- methylamino ethanol ester of Z-phenylbicyclo(2,2,1)heptane-Z-carboxylic acid of the formula C H O N boilingat 189-192 C./0.2 mm.

EXAMPLE 8 Z-Plzenyl Bicycl0(2,2,1)Heptane-Z-Carboxylic Acid-{3-Diethylamino Ethylamide A solution of 153 g. of Z-phenyl acrylonitrileand 118 g. of cyclopentadiene in 120 cc. of xylene to which 2 g. ofhydroquinone are added, is condensed as described hereinabove in Example2. The reaction mixture is worked up by following the procedure alsodescribed in said Example 2. The resulting 2-phenol-2-cyano bicyclo-(2,2,l)heptene of the formula C H N is a viscous oil of the boilingpoint 168-170 C./4 mm. It is converted by hydrogenation at roomtemperature and at atmospheric pressure in the presence of a platinumcatalyst into the saturated 2-phenyl-2-cyano -bi-cyclo(2,2,1)heptane.The solution of 150 g. of said nitrile in 175 cc. of ethanol and 120 cc.of 50% potassium hydroxide solution is heated in an autoclave at 150 C.for 8 hours. 250 cc. of water are added to the reaction mixture. Theethanol is removed by distillation in a vacuum and the alkaline solutionis acidified by the addition of hydrochloric acid. Thereby, the free2-phenyl bicyclo(2,2,1)heptane-Z-oarboxylic acid of the melting point148-149 C. precipitates.

By following the procedure, described hereinabove in Example 7, thecorresponding acid chloride is prepared by reacting said acid withthionylchloride.

A solution of 23.5 g. of the resulting acid chloride in 100 cc. oftoluene is boiled under reflux with 23.2 g. of diethylamino ethylaminefor 12 hours. After cooling, the reaction mixture is repeatedly shakenand extracted with 2-N hydrochloric acid. The acid extracts areneutralized by the addition of sodium hydroxide solution whereby 2phenyl bicyclo(2,2,l)heptane 2 carboxylic acid-fi-diethylaminoethylamide precipitates. It is dissolved in ether and is purified byfractional distillation. Its boiling point is 176179 C./0.3 mm. 'Itshydrochloride melts, on recrystallization from ethanol, at 193- 194 C.

EXAMPLE 9 (a) Z-Plzerzyl Bicycl0(2,2,1)-5-Heptene-2-Carb0xylic AcidDiet/zylamzno Ethyl Ester A solution of 69.5 g. of 2-phenyl acrylicacid-B-diethyh amino ethyl ester and 30 g. of cyclopentadiene in 30 cc.of xylene to which solution 0.2 g. of diphenylamine are added, iscondensed in an analogous manner as described hereinabove, in Example 2.The reaction mixture is extracted with dilute hydrochloric acid and,thereby, the basic reaction product is separated. On addition of dilutepotassium hydroxide solution to the acid aqueous extracts, a dark basicoil precipitates which is subjected to fractional distillation in avacuum. Thereby, 2-phenyl-bicyclo(2,2,1)heptene-Z-carboxylic aciddiethylamine ethyl ester of the formula C H O N is obtained. Said esteris a colorless oil of a weakly basic odor which boils at 152-155 C./O.3mm. Its hydrochloride melts, on recrystallization from a mixture ofethanol and ether (1:1) at 168-170 C. i

10 (b) Z-Phenyl Bicycl0(2,2,1)Hep tane-Z-Carboxylic Acid-B-DielhylaminoEthyl Ester Said unsaturated ester is dissolved in methanol and ishydrogenated in the presence of Raney nickel catalyst under pressure atroom temperature. Thereby the corresponding saturated basic ester of theformula C H O N is obtained in the form of a colorless oil which boilsat 164166 C./0.8 mm. I-ts hydrochloride melts, on recrystallization froma mixture of ethanol and ether (1:1), at 171-173 C.

EXAMPLE 10 Z-Phenyl Bicycl0(2,2,2)-5-Octene-2CarboxylicAcid-B-Diezhylzrmino Ethyl Ester A solution of 264 g. of 2-phenylacrylic acid ethyl ester and 128 g. of cyclohexadiene in 200 cc. ofxylene is heated in an autoclave with the addition of 2.5 g. ofhydroquinone as described hereinabove in Example 2. The reaction mixtureis worked up by following the procedure also described in said Example2. The resulting 2-phenyl bicyclo (2,2,2)-5-octene-2-carboxylic acidethyl ester of the formula C I-1 0 is a viscous refractive oil of theboiling point 163164 C./4 mm.

On reacting said ester with p-diethylamino ethanol as describedhereinabove in Example 2, 2-phenyl bicyclo (2,2,2)-5-octene-2-carboxylicacid-fl-diethylamino ethyl ester of the formula C H O N, is obtained.Said ester boils at 153-154 C./0.2 mm. Its hydrochloride melts, onrecrystallization from a mixture of ethanol and ether (1:1 at 142-143 0.

EXAMPLE 11 Y Z-Phenyl-7-Is0propyl-6-M ethyl Bicycl0( 2,2,2 Octane-Z-Carboxylic Acid-[i-Diethylamino Ethyl Ester A solution of 380 g. of2-phenyl acrylic acid ethyl ester and4-isopropyl-1-methyl-2,6-cyclohexadiene in 250 cc. of xylene iscondensed with the addition of 4 g. of hydroquinone as describedhereinabove in Example 2. The reaction mixture is worked up by followingthe procedure also described in said Example 2. The resulting 2-phenyl-7-isopropyl-6-methyl bicyclo(2,2,2)-5-octene-2-carboxylic acid ethylester of the formula C H O boils at 179181 C./4 mm. It is a viscousrefractive oil.

On hydrogenation of said ester in methanolic solution and in thepresence of Raney nickel catalyst as described hereinabove in Example 6,the corresponding saturated ester of the formula C H O and the boilingpoint 176- 178 C./ 4 mm. is obtained. On saponifiying said ester asdescribed hereinabovein Example 7, the free 2-phenyl-7- isopropyl6-methyl -bicyclo(2,2,2)octane 2 carboxylic acid of the formula C H O isprepared. Said acid boils at 165170 C./0.6 mm. and has a melting pointof "v C. on recrystallization from a mixture of methanol and water(1:1).

28.6 g. of said acid are added to a solution of 2.3 g. of metallicsodium in cc. of isopropanol. 17.2 g. of fi-diethylamino ethylchloridehydrochloride are added to said solution. The reaction mixture is boiledunder reflux for 8 hours. The precipitated sodium chloride is removed byfiltration and the filtrate is concentrated by evaporation in a vacuumon a water bath. The residue is dissolved in water and the basic esteris precipitated from the resulting aqueous solution by the addition ofpotassiume carbonate solution. The precipitated fi-diethyl amino ethylester of 2-phenyl-7-isopropyl-6-methyl bicyclo(2,2,2)octane-2-carboxylic acid of the formula C H O N is an almostodorless, viscous, refractive oil of the boiling point 206-209 C./3 mm.Its hydrochloride is highly hygroscopic.

In place of Z-methylbutadiene and 2,4-dimethylbutadione as they are usedas diene compounds in Examples 2 and 3, there may be employedequimolecular amounts of butadiene compounds containing other alkylradicals. The cyclopentadiene and the cyclohexadiene compounds used inthe preceding examples may also be replaced by equimolecular amounts ofother alkyl, cycloalkyl, aryl, and aralkyl substituted cyclopentadieneand cyclohexadiene compounds. Otherwise the procedure is the same asthat described in the examples given hereinabove. However, the compoundsprepared according to said examples and especially the cyclopentadienereaction products of Examples 5, 6, and 7, have proved to be of specialvalue.

In place of the diethylamino and dimethylamino ethyl and propyl alcoholsor ethyl and propyl halogenides used in the examples, there may beemployed equimolecular amounts of other tertiary amino alcohols andamino alkyl halogenides.

In place of the hydrochlorides there may be prepared other acid additionsalts with inorganic or organic acids such as the hydrobromides,sulfates, phosphates, amidosulfonates, acetates, citrates, tartrates,benzoates, malates, and the like provided the acid components of suchacid addition salts are tolerated by the human body in the concentrationin which they are administered.

Likewise, in place of the methosulfates, there may be prepared otherquaternary ammonium compounds of the new basic esters and amides such asthe alkochlorides, the alkobromides, the alkyl toluene sufonates, andothers.

As stated hereinabove, compounds of the following groups'are especiallyvaluable compounds:

(a) 2-phenyl bicyclo(2,2,1)heptane-Z-carboxylic acidw-tertiary aminoalkyl esters such as the 2-phenyl bicyclo- (2,2,1 )heptane 2 carboxylicacid diethylamino propyl ester of Example 7.

(b) 2 -phenyl bicyclo(2,2,1)heptane-Z-carboxylic acid esters withheterocyclic alcohols and especially the 2- phenylbicyclo(2,2,1)heptane-Z-carboxylic ester tropinol ester and the Z-phenylbicyclo(2,2,l)heptane-Z-carboxylic acid N-methyl-4-piperidol ester inthe form of its methosulfate. 7

The basic esters or amides according to the present invention areadministered orally or parenterally. Preferably they are not used intheir original form but diluted, thus allowing better and moreeconomical use to be made thereof. They are preferably administeredorally in the form of shaped solid preparations of their salts orquaternary ammonium compounds such as the hydrochlorides or themethosulfates. Suitable forms for oral administration are tablets,pills, dragees, capsules or the like shaped preparationsQ Solutions,emulsions, suspensions, dispersions, or similar forms of applicationmay, of course, also be used.

In the case of powders, a fine dispersion of the active compound is ofimportance. Such a fine dispersion can be achieved, for instance, byintimately mixing and milling the compound in a ball mill with a solid,pulverulent extending agent, to the desired degree of fineness or byimpregnating the already milled, finely powdered, solid carrier with amixture of the active compound in water or any other suitable solventand then removing the water or solvent.

When preparing tablets, pills, powders, and the like preparations to beused in human therapy, commonly used diluting agents, binders,lubricants, and other tableting adjuvants are employed, such as sugar,lactose, talcum, starch, bolus alba, pectin, as binders gelatin, gumarabic, methyl cellulose, yeast extract, agar, tragacanth, and aslubricants stearic acid, magnesium stearate, and others. The content ofactive compounds in such preparations may vary. It is, of course,necessary that the active compound be present in such an amount that asuitable dosage will be ensured. Ordinarily the preparation should notcontain less than 1 mg. of the active compound. The preferred amount ofthe active compound to be employed is between 0.1% and 1% of thepreparation. To use greater amounts is also possible, althoughadministration of the suitable dose becomes more difficult. Tabletscontaining, for instance, between about 1 mg. and about 5 mg. andpreferably about 2 mg. of the active compound per tablet have proved tobe especially suitable. Such tablets of 2-phenyl bicyclo(2,2,1)heptane 2carboxylic acid diethylamino propyl ester have successfully been used intherapy.

The tropinol ester of Z-phenyl bicyclo(2,2,1)heptane- 2-carboxylic acid,which is noteworthy by its remarkable antiphlogistic activity, ispreferably used in the form of an ointment for the treatment ofinflammatory skin diseases. Ointments containing about 0.5% of saidcompound in an ointment base known to the art by the trademark Eucerinhas proved to be especially suitable. Said Eucerin base consists ofemulsified wool fat alcohols with 2% of cholesterol and aliphatichydrocarbons, such as Vaseline or paraflin, mixed and emulsified withwater.

Of course, many changes and variations in the 2-phenyl acrylic acidstarting material, the diene compounds, the

solvents, the polymerization inhibitors, the hydrogenation catalystsused, in the reaction conditions, temperature, duration, pressure, inthe intermediate acids and acid derivatives such as esters, nitriles,chlorides, and the like employed, in the basically substituted reactioncomponents, in the methods of isolating, working up, and purifying thereaction products and converting them into their acid addition salts andtheir quaternary ammonium compounds, in the manner of therapeuticallyadministering the new compounds and of preparing therapeuticallyeffective preparations, and the like may be made by those skilled in theart in accordance with the principles set forth herein and in the claimsannexed hereto.

We claim:

1. The Z-phenyl bicyclo'(2,2,l)heptane-Z-carboxylic acid-'y-diethylaminopropyl ester.

2. The Z-pheuyl bicyclo(2,2,1)heptane-Z-carboxylic acid tropinol ester.

3. The Z-phenyl bicyclo( 2,2,1)heptane-Z-carboxylicacid-N-methyl-4-piperidol ester methosulfate.

4. 2-phenyl bicyclo(2,2;l)heptane-Z-carboxylic lower alkyl esters of theformula acid wherein R is a lower alkyl radical.

5. The 2-phenyl bicyclo(2,2,1)heptane-Z-carboxylic acid chloride of theformula 13 6. The 2-phenyl-2-cyano bicyclo(2,2,1)heptane of the formula7. 2-phenyl bicyclo(2,2,l)--heptene-2-carboxylic acid of the formulaCOOH 8. Z-phenyl bicyclo(2,2,l)heptane-Z-carboxylic acid of the formulaOOOH 9. The 2-phenyl bicyclo(2,2,l)heptane-Z-carboxylic acid pyrrolidinoethyl ester.

10. The 2-phenyl bicyclo(2,2,1)heptane-Z-carboxylic acid N-loweralkyl-4-piperidol esters.

11. Lower alkyl esters of 2-phenyl bicyclo(2,2,1)-5-heptene-Z-carboxylic acid.

12. Z-phenyl bicyclo(2,2,2)octane-2-carboxylic acid.

13. Di-(lower alkyl)amino lower alkyl esters of 2- phenylbicyclo(2,2,1)heptane-2-carboxylic acid.

14. Lower alkyl esters of 2-phenyl bicyclo(2,2,2)-5- octene-Z-carboxylicacid.

15. In a process of producing carboxylic acid compounds of the formulaCOOX--N s wherein X is an alkylene radical having 2 to 3 carbon atoms,and R and R are members selected from the group consisting of loweralkyl radicals and, together with the nitrogen atoms to which they areattached, the piperidyl, morpholinyl, and pyrrolidyl radicals; and thecarboxylic acid w-amino lower'alkyl amide group of the formula whereinX, R and R represent the same members as indicated above; and R and Rindicate members selected from the group consisting of hydrogen and alower alkyl radical; the steps which comprise heating a phenyl acrylicacid compound of the formula wherein Z is the same member as indicatedabove, with a diene compound selected from the group consisting ofcyclopentadiene, cyclohexadine, and lower alkyl substitutedcyclopentadienes and cyclohexadienes in the presence of a polymerizationinhibitor in a solution in an inert solvent and under pressure andhydrogenating the double bond in the resulting bicyclo-alkene compound.

References Cited in the file of this patent UNITED STATES PATENTS2,404,588 Martin July 23, 1946 2,704,284 Weston Mar. 15, 1955 FOREIGNPATENTS 249,054 Switzerland Mar. 16, 1948

2. THE 2-PHENYL BICYCLO (2,2,1) HEPTANE-2-CARBOXYLIC ACID TROPINOLESTER.
 15. IN A PROCESS OF PRODUCING CARBOXYLIC ACID COMPOUNDS OF THEFORMULA